tbuckley/cabot-search huggingface dataset:
P08.07.A Long-term multidimensional assessment of fatigue and fatigue as predictor of survival in patients with brain metastases after Gamma Knife radiosurgery
Authors: E Verhaak, W Schimmel, E Butterbrod, M Sitskoorn, P Hanssens, K Gehring
Journal: Neuro-Oncology (2022)

Abstract Background The aim of this study was to assess long-term multidimensional fatigue and (change in) fatigue as predictor for survival in patients with brain metastases (BM) up to 21 months after Gamma Knife radiosurgery (GKRS). Material and Methods Patients with 1 to 10 BM, expected survival &amp;gt;3 months, and Karnofsky Performance Status ≥70 were included. Fatigue was measured with the Multidimensional Fatigue Inventory (MFI). Linear mixed models were used to evaluate fatigue up to 21 months after GKRS. Fatigue before GKRS and changes in fatigue in the first three months after GKRS were evaluated as predictors for survival duration. Results Patients with BM experienced significantly higher levels of fatigue on all subscales prior to GKRS (n=92) compared to Dutch controls (n=104), all p’s≤.001. Over 21 months, levels of physical fatigue increased significantly (p=.001), and levels of mental fatigue decreased significantly (p=.004). Between pre-GKRS and 3 months, there was a significant increase in levels of general (p&amp;lt;.001) and physical fatigue (p&amp;lt;.001), followed by stable fatigue scores between 3 (n=67) and 6 (n=53) months, 6 and 12 (n=34) months and 12 and 21 (n=21) months. Minimal clinically important (MCI) increases in general (p=.023, time ratio=0.61) and in physical fatigue (p=.008, time ratio=0.56) from pre-GKRS to 3 months thereafter were independent negative predictors of survival time (i.e., an MCI increase in these domains predicted a reduction of 39% and 44% respectively in survival time compared to stable or decreased fatigue). Conclusion Results indicate that up to 21 months after GKRS fatigue is a persistent problem in patients with BM. Except for an increase in general and physical fatigue up to 3 months after treatment, fatigue remained stable up to 21 months after GKRS. In addition, an MCI increase in general or physical fatigue within three months after GKRS may be related to worse survival outcome.
P07.07.A Fluorescence lifetime imaging for improved visualization of 5-ALA fluorescence during biopsies of suspected brain tumors
Authors: M Millesi
Journal: Neuro-Oncology (2022)

Abstract Background Stereotactic brain tumor biopsies represent a standard neurosurgical technique enabling a precise histopathological tumor diagnosis which is of utmost importance for optimal further treatment allocation. However, non-diagnostic biopsies are not uncommon in routine clinical practice. To overcome this shortcoming, serial biopsies or intraoperative histopathology are typically performed prolonging the operating times and potentially increasing the risk of complications. Recently, the value of 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence for visualization of diagnostic tumor tissue was demonstrated in navigation-guided brain tumor biopsies. However, a not negligible proportion of brain tumors lack visible fluorescence. In some of these tumors, a subvisual concentration of PpIX could be detected by spectroscopic analysis. Thus, detection of such subvisual PpIX accumulation in tumor samples in biopsies by the new “Fluorescence Lifetime Imaging” (FLIM) technique might lead to further improvement of this approach. Material and Methods Patients that underwent navigation-guided biopsy of a suspected brain tumor were eligible for inclusion in this study. After administration of 5-ALA, the tissue samples were checked for visible fluorescence during the navigation-guided stereotactic biopsy with a sterile microscope. In each sample the observed fluorescence signal was documented. Additionally, the tissue samples were investigated ex-vivo by FLIM for detection of PpIX accumulation. In each case, a histopathological diagnosis was established according to the WHO classification of CNS tumors. Results A total number of 20 tissue samples could be retrieved in 16 patients with suspected brain tumors. The biopsy with assistance of 5-ALA was feasible in all patients and no relevant side effects occurred. Visible PpIX fluorescence could be observed in 75% of cases. In contrast, 25% of samples did not show visible fluorescence. In one specimen, no fluorescence signal could be evaluated as the sample was covered by too much blood. However, significant accumulation of PpIX could be detected by FLIM in all samples in which evaluation was possible (n=19). A final histopathological diagnosis was feasible in all patients. Conclusion Fluorescence Lifetime Imaging is a promising new technique for improved detection of brain tumor tissue during navigation-guided biopsies. Thus, this new technique might lead in future to reduced operating times and complication rate by minimizing the cases that need serial biopsies or intraoperative histopathology.
P09.06.B The effectiveness of antiepileptic drug tripletherapy in refractory epileptic glioma patients: a multicenter observational cohort study
Authors: P B van der Meer, L Dirven, M Fiocco, M J Vos, M C M Kouwenhoven, M J van den Bent, M J B Taphoorn, J A F Koekkoek
Journal: Neuro-Oncology (2022)

Abstract Background About 10% of the glioma patients need antiepileptic drug (AED) tripletherapy due to refractory epilepsy. This study aimed to determine whether levetiracetam combined with valproic acid and clobazam (LEV+VPA+CLB), a commonly prescribed tripletherapy, has favourable effectiveness compared to other tripletherapy combinations in glioma patients. Material and Methods In this multicenter retrospective observational cohort study, the primary outcome was the cumulative incidence of treatment failure for any reason, from initiation of AED tripletherapy. Secondary outcomes included cumulative incidences of: 1) treatment failure due to uncontrolled seizures; 2) treatment failure due to adverse effects; and 3) recurrent seizure. Maximum duration of follow-up was 36 months. Results Ninety patients, from an initial cohort of n=1435 patients, received AED tripletherapy after second-line AED duotherapy treatment failure due to uncontrolled seizures. LEV+VPA+CLB was prescribed to 43 (48%) and other AED tripletherapy to 47 (52%) patients. The cumulative incidence of treatment failure for any reason of LEV+VPA+CLB did not significantly differ from other tripletherapy combinations (12 months: 47% [95%CI, 31-62%] versus 42% [95%CI, 27-56%], p=0.892). No statistical significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95%CI, 4-25%] versus 18% [95%CI, 8-30%], p=0.445), due to adverse effects (12 months: 22% [95%CI, 11-36%] versus 15% [95%CI, 7-27%], p=0.446), or recurrent seizure (1 month: 65% [95%CI, 48-78%] versus 63% [95%CI, 47-75%], p=0.911) were found. Conclusion LEV+VPA+CLB has not shown favourable efficacy or tolerability compared to other AED tripletherapy combinations in glioma patients. Therefore, we cannot specifically recommend CLB as tripletherapy add-on AED to LEV+VPA.
P18.07.A Hippo signaling pathway is strongly involved in meningioma tumorigenesis
Authors: Gregory Mougel, Grégoire Mondielli, R Appay, Adeline Querdray, C Roche, A Jijon, I Konstantinova, A Soude, Thomas Graillon, Anne A. Barlier
Journal: Neuro-Oncology (2022)

Abstract Background Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In mammals, Hippo signaling pathway is responsible for the growth of organs by regulating cell proliferation and apoptosis. The tumor suppressor NF2 protein belongs to the core of the Hippo pathway and a defect of its gene is present in 50% of meningiomas. Absence of NF2 keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the nucleus and the formation of a complex with TEADs. This complex then promotes the transcription of anti-apoptotic and proliferative genes such as CTGF, CYR61 and AXL. Here we present experimental results on human meningioma fragments and primary cell cultures supporting that Hippo pathway plays a critical role in meningioma tumorigenesis. Material and Methods The role of the Hippo pathway was studied on 57 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and TEADs. Results Fifty-seven meningiomas were randomly selected including 27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2 gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented a significant increase of expression levels of Hippo pathway target transcripts CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p&amp;lt;0.0001, p=0.0072 and p=0.0191, respectively). This increase was not correlated with the grade, the sex or with the cerebral localization of the meningiomas. On the other side, IHC analysis suggested this increase was correlated with the nuclear localization of YAP. Disturbing the YAP/TAZ-TEADs complex using siRNA on 10 meningiomas (5 NF2 wild-type and 5 NF2 def) induced a significant decrease on cell proliferation but not on cell viability. This decrease was more important when TAZ was turned off in comparison to turning off of YAP. Conclusion Our experimental results strongly support the importance of the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a new target in meningioma therapy. A.Barlier reports receiving research grants from Inventiva Pharma. No potential conflicts of interest were disclosed by the other authors.
P11.48.A Primary CNS lymphoma after CLIPPERS: a case series
Authors: S Doubrovinskaia, F Sahm, M C Thier, M Bendszus, W Wick, C Seliger, L D Kaulen
Journal: Neuro-Oncology (2022)

Abstract Background Few cases of primary CNS lymphoma(PCNSL) following a diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) are reported in the literature. Here we explore implications of this sequel for CLIPPERS follow-up and PCNSL outcome. Material and Methods A systematic review and meta-analysis of previously described cases in the MEDLINE database was performed in compliance with PRISMA guidelines. Clinical, radiological and pathological characteristics were summarized. Overall survival was estimated using the Kaplan-Meier method. Results In addition to a case from our institution, nine cases were previously described in the literature. Eight patients fulfilled diagnostic criteria for ‘definite’ CLIPPERS whereas two cases were diagnosed with ‘probable’ CLIPPERS. Male-to-female ratio was 9:1. Median interval from CLIPPERS to PCNSL diagnosis was 4.5 months. All patients had received immunosuppressive therapy including methylprednisone in all and azathioprine or cyclophosphamide in most cases. On MRI, appearance of a larger lesion (&amp;gt;3mm) with peripheral contrast enhancement was noted in the most cases upon PCNSLdiagnosis. Whereas Epstein-Barr virus was not detected in biopsy specimen upon CLIPPERS diagnosis, it was identified in the majority of samples upon PCNSL diagnosis. Treatmentfor PCNSL included high-dose methotrexate basedchemotherapy in most cases, however median overall survival was poor (5.5 months). Conclusion Interval from CLIPPERS to PCNSL diagnosis was short and may mandate close clinical and radiological follow-up, specifically within the first two years after CLIPPERS diagnosis. Characteristics of PCNSL following CLIPPERS resemble other immunodeficiency-related PCNSL. Outcome was inferior and may reflect late diagnosis or brainstem localization.
P11.47.B A description of inpatient admissions of adult glioblastoma patients in England 2103 - 2018 from the GlioCova project
Authors: K Le Calvez, R Mauricaite, M Williams
Journal: Neuro-Oncology (2022)

Abstract Background The Gliocova dataset uses linked English national cancer data on all 51,775 adult primary brain tumour patients diagnosed between 2013-2018. Here we present early analysis of inpatient admissions of adult glioblastoma (GBM) patients. Material and Methods We identified all adults patients diagnosed with a GBM and extracted all the inpatient admissions for 1 night or more after the date of diagnosis. We focused on number and length of admissions, variation in those numbers, and place of discharge. Results Between 2013 and 2018, 15,294 patients were diagnosed with a glioblastoma in England (60% male) with a median age of 66, of whom, 12,441 (61% male) were admitted overnight with a total of 49,384 admissions post-diagnosis. Half of these patients were less than 64 at the time of their admission. The mean number of post-diagnosis admissions was 4, with a mean length of stay of 9.5 days. However, for half of the admissions, patients stayed 5 days or less in hospital (IQR = 10). Most of the procedures done were treatment-related, such as surgery for which patients stayed an average of 6.3 days (median = 4; IQR = 5). Patients who were admitted for non-treatment reasons stayed on average almost 10 days (median = 5; IQR = 11). Fewer than 3,000 admissions resulted in a patient death (5.5% of all admissions), whereas over 23,000 admissions for 10,426 patients ended with patients being discharged at home. About 2,000 patients were discharged to another hospital, hospice or a nursing home. Conclusion Most of the patients diagnosed with a glioblastoma will be admitted at some point after their diagnosis. Although the average length of stay is not that long, there is a considerable tail of longer-staying patients, for whom improved services and support might enable quicker discharge. To our knowledge, this is the first time inpatient admissions in adult brain patients are being looked at.GlioCova is supported by the Imperial/NIHR BRC, and the members of the GlioCova EAG. This work uses data provided by patients and collected by the NHS as part of their care and support.More information on the Gliocova project can be found on https://blogs.imperial.ac.uk/gliocova.
P07.05.A Implantable electrophoretic devices for local treatment of inoperable brain tumours
Authors: M H Ahmed, T Naegele, S Hilton, G Malliaras
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most malignant primary brain tumour in adults, with a median overall survival of fewer than 18 months after initial diagnosis. For over five decades, research has been focused on developing new anticancer therapies for GBM, including anti-neoplastic agents, molecular targeted drugs, immunotherapeutic approaches, and angiogenesis inhibiting compounds; however, the prognosis of patients has hardly improved and temozolomide remains the only chemotherapy shown to improve patient survival in randomized clinical trials. A fundamental limitation of the success of chemotherapy in brain cancer therapies is the blood-brain barrier which significantly reduces the concentration of chemotherapeutic agents delivered into a tumour. Material and Methods Therapeutic strategies that control drug release spatially and temporally represent a significant step forward in terms of reducing side effects and improving treatment efficacy and will thus have a significant clinical impact. Electrophoretic drug delivery devices, which use electric fields to enhance drug transport, represent one such strategy. Results Here, we present an implantable device that enables highly spatially selective delivery of charged drug molecules directly into brain tumours. Our device combines a microfluidic system for drug transport with embedded electrodes which enable electrophoretic transport of drug molecules into the target tissue. This allows delivery of chemotherapeutic agents without transport of bulk solvent preventing issues arising from intracranial pressure gradients. We have shown that the device can be implanted safely without any limitation. We have tested the device's capabilities to deliver a wide range of small, medium, and large chemotherapeutic agents without limitations. Currently, we are investigating the delivery of cisplatin in GBM-bearing mice. Conclusion While electrophoretic drug delivery was first described in the early 20th century and has been used since primarily for transdermal drug delivery, we believe that our approach is one of the first times this has been demonstrated for brain cancer therapy.
P03.05.A Radiation-induced leukoencephalopathy (RIL) in glioma: unique injury dynamics following proton vs photon beam radiotherapy
Authors: S F Winter, M Gardner, M W Parsons, C Grassberger, M Bussière, D Kaul, W Boehmerle, M Endres, H A Shih, J Dietrich
Journal: Neuro-Oncology (2022)

Abstract Background White matter injury after brain-directed radiotherapy (RT), aka radiation-induced leukoencephalopathy (RIL), is common in brain tumor patients. Differentiation from progressive disease can be challenging. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain tissue, potentially limiting radiotoxic sequelae including RIL. We characterized RIL during periods of progression-free survival (PFS) in glioma patients irradiated with either PRT or XRT, hypothesizing that PRT would result in reduced RIL outside of the target field. Material and Methods 34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas and a history of partial cranial RT were stratified by RT modality [XRT (n=17) vs PRT (n=17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospective analysis. RIL development was characterized longitudinally for up to 3 years post-RT via analysis of serial MRI T2/FLAIR sequences. A novel RIL scoring system with embedded Fazekas scale was designed to quantify injury severity at both global (whole brain) and hemispheric levels. Results Matched groups did not differ significantly on any demographic or clinical characteristics. Median PFS post-RT was 4.7 (XRT) and 5.1 (PRT) years. The novel RIL scoring system was reliable (intraclass correlation coefficient &amp;gt;0.9). There was a significant increase in global RIL in both XRT [F(3, 57)=8.63, p&amp;lt; .001] and PRT [F(3, 61)=4.69, p&amp;lt; .005] groups over time, relative to baseline (1-month post-RT). A majority [62% (XRT) and 72% (PRT)] developed moderate or severe RIL within 3 years, with the ipsilesional hemisphere more severely affected. Analysis of RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) at hemispheric level identified radiation modality-specific differences: XRT resulted in greater contralesional hemispheric injury than PRT [F(1, 31)=4.32, p&amp;lt;.05]. This effect was not observed in ipsilesional hemispheres. Conclusion RIL is common in glioma patients and quantifiable by characteristic imaging features, including early onset post-RT, greater ipsilesional injury burden, and progression over time. RIL injury dynamics appear to be radiation modality-specific, whereby XRT causes greater delayed injury in the remote, contralesional hemisphere. These findings may reflect dosimetric differences between protons and photons. The impact of such sequelae on cognitive function is subject of current investigation.
P11.49.B MOG antibody positive paraneoplastic brain stem encephalitis associated with cervical cancer: a rare case report
Authors: L Bieler, C Hecker, L Machegger, P Wolfrum-Ristau, E Trinka, W Kleindienst
Journal: Neuro-Oncology (2022)

Abstract Background Paraneoplastic neurological syndromes are a rare complication of malignant tumors. Myelin oligodendrocyte glycoprotein (MOG) is an important marker on the surface of oligodendrocytes and is associated with many demyelinating diseases. There are only few reports of MOG antibody positive paraneoplastic syndromes. Here we present the first case of MOG-antibody positive brain stem encephalitis associated with cervical cancer. Material and Methods: Case report. Results A 58-year-old female presented with headache, fever and acute cerebellar signs. 13 months earlier she was diagnosed with cervical cancer and ovarian metastases. Adnexectomy was performed and she received adjuvant chemo- and radiotherapy. At admission cerebrospinal fluid (CSF) analysis showed pleocytosis (90 cells/µl) with a mixed cell profile but no malignant cells could be detected. Protein and lactate were highly elevated. The patient was treated with aciclovir and ceftriaxone until serology and liquor PCR showed no evidence of systemic or cerebral infections. Initial magnetic resonance imaging (MRI) of the brain was unremarkable. The patient was symptomatically treated. CSF two weeks later showed 53 cells/µl, protein and lactate almost normal. Contrary to the mild improvement of CSF parameters, cerebellar symptoms worsened, and the patient complained about impaired vision and diplopia. MRI revealed gadolinium enhancing lesions of the left mesencephalon and the right N. opticus. Visual evoked potentials confirmed a demyelinating lesion of the right N. opticus. We then assumed paraneoplastic brain stem encephalitis and the patient received high dose methylprednisolone and immunoglobulins. Ultimately, lab results came back positive for anti-MOG-antibodies, while paraneoplastic panels were negative. At follow-up three weeks later, CSF analysis showed normal cell count and brain MRI was unremarkable again. MOG-antibodies however remained positive. Since then, the patient has received monthly immunoglobulins leading to a stable neurological status. Unfortunately, the cancer itself is progressive with a local relapse and metastases of liver, lung and bones. Conclusion Our patient had an acute presentation of a rare brain stem encephalitis. However, infectious workup as well as all well-known onconeural antibodies showed negative results. This shows that pleocytosis in patients with a history of malignant disease is highly suggestive for paraneoplastic neurological syndromes even if common antibodies show negative results. Clinicians should be aware of other autoimmune antibodies like anti-MOG-antibodies and should extend workup if necessary. Vice versa it is worth considering tumor workup in patients with neurological symptoms and anti-MOG-positivity. Furthermore, the appearance of paraneoplastic neurological syndromes is always suspicious for progressive disease.